Brand Names: U.S.

Cytotec

Pharmacologic Category

Prostaglandin

Pharmacology

Misoprostol is a synthetic prostaglandin E1 analog that replaces the protective prostaglandins consumed with prostaglandin-inhibiting therapies (eg, NSAIDs); has been shown to induce uterine contractions

Absorption

Rapid and extensive; food decreases absorption of misoprostol acid

Metabolism

Hepatic; rapid de-esterification to misoprostol acid (active)

Excretion

Urine (80%)

Onset of Action

Inhibition of gastric acid secretion: 30 minutes

Time to Peak

Serum: Misoprostol acid: Fasting: 12 ± 3 minutes

Duration of Action

Inhibition of gastric acid secretion: 3 hours

Half-Life Elimination

Misoprostol acid: 20 to 40 minutes

Protein Binding

Misoprostol acid: <90%

Special Populations: Renal Function Impairment

Cmax, AUC, and t½ are almost doubled, but no clear correlation between degree of impairment and AUC is shown.

Special Populations: Elderly

AUC is increased in patients >64 years of age.

Use: Labeled Indications

NSAID-induced gastric ulcers, prevention: To reduce the risk of NSAID-induced gastric ulcers in patients at high risk of complications

Off Label Uses

Cervical ripening and labor induction

Based on the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 107: Induction of Labor, misoprostol tablets administered intravaginally for cervical ripening and labor induction is effective and recommended in the management of this condition [ACOG 107 2009].

Early pregnancy loss

Based on the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 150: Early Pregnancy Loss, misoprostol given for early pregnancy loss is effective and recommended for patients who desire to shorten the time to complete expulsion and prefer to avoid surgical evacuation [ACOG 150 2015].

Incomplete or missed abortion (treatment)

Based on the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 427: Misoprostol for Postabortion Care, misoprostol given for treatment of incomplete or missed abortion in women <12 weeks gestation is effective and recommended in the management of this condition [ACOG 427 2009].

Postpartum hemorrhage (prevention/treatment)

Based on the International Federation of Gynecology and Obstetrics (FIGO) Prevention of Postpartum Hemorrhage With Misoprostol guidelines and the FIGO Treatment of Postpartum Hemorrhage With Misoprostol guidelines, misoprostol given for the prevention and treatment of postpartum hemorrhage is effective and recommended in the management of this condition [FIGO, 2012a], [FIGO, 2012b].

Contraindications

Hypersensitivity to misoprostol, other prostaglandins, or any component of the formulation; pregnancy

When used for termination of intrauterine pregnancy (additional contraindications): Refer to Mifepristone monograph.

Early pregnancy loss (off-label use): Intravaginal (off-label route): Initial dose: 800 mcg. May repeat with one dose if needed, ≥3 hours after the first dose and typically within 7 days if no response to the initial dose is observed (ACOG 150 2015).

Note: The vaginal route may be more efficient; however, some adverse events may occur less frequently when misoprostol is administered orally for this indication (ACOG 107 2009; Alfirevic 2014; Chen 2016; Kundodyiwa 2009). Sublingual and buccal routes should not be used for cervical ripening or induction of labor (ACOG 107 209). Additional data may be necessary to further define the optimal dose and route of administration.

Postpartum hemorrhage (prevention) (off-label use): Note: Side effects are associated with use and may be dose and route related (Leduc 2009; Ugwu 2016). Additional data may be necessary to further define the optimal dose and route of administration (Bolhmann 2014).

Oral: 600 mcg as a single dose administered immediately after delivery (FIGO 2012a).

Postpartum hemorrhage (treatment) (off-label use): Note: Side effects are associated with use and may be dose and route related (FIGO 2012b; Leduc 2009). Additional data may be necessary to further define the optimal dose and route of administration (Bolhmann 2014).

Sublingual (off-label route): 800 mcg as a single dose. Use caution if a prophylactic dose was already given, especially if adverse events were observed (FIGO 2012b). Dosage ranges of 600 to 1,000 mcg as a single dose have been noted (ACOG 183 2017), however a lower 400 mcg dose has also been recommended (Leduc 2009).

Dosing: Geriatric

NSAID-induced gastric ulcers, prevention: Refer to adult dosing.

Dosing: Pediatric

Termination of intrauterine pregnancy: Oral: Refer to adult dosing.

Dosing: Renal Impairment

Dose adjustment is not routinely needed; however, the dose may be reduced if the recommended dose is not tolerated. It is not known if misoprostol is removed by dialysis.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Administration

Administer with food and avoid magnesium containing antacids (minimizes diarrhea); last dose of the day should be taken at bedtime. Therapy should continue through the duration of NSAID therapy.

Oxytocin: MiSOPROStol may enhance the adverse/toxic effect of Oxytocin. Specifically, oxytocic effects may be enhanced. Management: The manufacturer of misoprostol recommends avoiding concomitant use with oxytocin. Misoprostol may augment effects of oxytocin, particularly when given within 4 hours of oxytocin initiation. Consider therapy modification

Phenylbutazone: May enhance the neurotoxic effect of MiSOPROStol. Specifically, the combination may result in headache, dizziness, and transient diplopia. Monitor therapy

ALERT: U.S. Boxed Warning

Women of childbearing potential:

Misoprostol administration to women who are pregnant can cause birth defects, abortion, premature birth, or uterine rupture. Uterine rupture has been reported when misoprostol was administered in pregnant women to induce labor or to induce abortion. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including cesarean delivery. Misoprostol should not be taken by pregnant women to reduce the risk of ulcers induced by NSAIDs.

Patients must be advised of the abortifacient property and warned not to give the drug to others.

Misoprostol should not be used for reducing the risk of NSAID-induced ulcers in women of childbearing potential unless the patient is at high risk of complications from gastric ulcers associated with use of the NSAID, or is at high risk of developing gastric ulceration. In such patients, misoprostol may be prescribed if the patient has had a negative serum pregnancy test within 2 weeks prior to beginning therapy; is capable of complying with effective contraceptive measures; has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential if the drug is taken by mistake; and will begin misoprostol only on the second or third day of the next normal menstrual period.

Warnings/Precautions

Concerns related to adverse effects:

• Abortifacient: [US Boxed Warning]: Due to the abortifacient property of this medication, patients must be warned not to give this drug to others.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be needed.

Special populations:

• Pregnancy: Adverse events have been reported when used outside of current product labeling (cervical ripening, induction of labor, treatment of serious postpartum hemorrhage). Uterine tachysystole may occur and progress to uterine tetany; uteroplacental blood flow may be impaired and uterine rupture or amniotic fluid embolism leading to adverse fetal heart changes may occur. The risk of uterine rupture may be increased with advanced gestational age, grand multiparity, or prior uterine surgery (including cesarean delivery). Uterine activity and fetal status should be monitored in a hospital setting. Misoprostol should not be used in situations where uterotonic drugs are otherwise contraindicated or inappropriate.

• Women of childbearing potential: [US Boxed Warning]: Use of misoprostol during pregnancy may cause birth defects, abortion, premature birth, or uterine rupture. Uterine rupture has been reported when misoprostol was administered in pregnant women to induce labor or to induce abortion. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including cesarean delivery. Misoprostol is not to be used to reduce the risk of NSAID-induced ulcers in woman of childbearing potential unless she is at risk of complications from gastric ulcers associated with NSAID use, or is at high risk of developing gastric ulceration. In such patients, misoprostol may be prescribed if the patient has had a negative serum pregnancy test within 2 weeks prior to beginning therapy; is capable of complying with effective contraceptive measures; has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential if the drug is taken by mistake; and will begin misoprostol only on the second or third day of the next normal menstrual period. Due to the abortifacient property of this medication, patients must be warned not to give this drug to others.

• Appropriate use: Termination of pregnancy: Misoprostol is approved for use with mifepristone for termination of pregnancy. Refer to mifepristone warnings, precautions, and contraindications for appropriate use of misoprostol for this indication.

• Appropriate use: Gastric ulcers: For use only in patients at high risk of complications from gastric ulcers (eg, elderly patients, patients with concomitant diseases) or patients at high risk for developing gastric ulcers (eg, those with a history of ulcers) taking NSAIDs. Misoprostol must be taken during the duration of NSAID therapy. It is not effective in preventing duodenal ulcers in patients taking NSAIDs.

Monitoring Parameters

Off-label pregnancy-related uses: Uterine activity and fetal status. When used for incomplete or missed abortion, reevaluate 1 to 2 weeks after dosing (ACOG 427 2009). When used for termination of pregnancy: Prior to procedure, confirm pregnancy and Rh status; assess hemoglobin and hematocrit if anemia is suspected (ACOG 2014). Following procedure: Clinical exam, human Chorionic Gonadotropin (hCG) testing, and/or ultrasound to confirm complete termination of pregnancy; hemoglobin, hematocrit, and red blood cell count in cases of heavy bleeding. Consider CBC in any patient who reports nausea, vomiting, or diarrhea and weakness with or without abdominal pain, and without fever or other signs of infection more than 24 hours after administration of misoprostol (Mifeprex prescribing information March 2016).

Pregnancy Considerations

Use for the prevention of NSAID-induced gastric ulcers is contraindicated in pregnant women.

[US Boxed Warning]: Use of misoprostol during pregnancy may cause birth defects, abortion, premature birth, or uterine rupture. Uterine rupture has been reported when misoprostol was administered in pregnant women to induce labor or to induce abortion. The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including cesarean delivery. Misoprostol is not to be used to reduce the risk of NSAID-induced ulcers in woman of childbearing potential unless she is at risk of complications from gastric ulcers associated with NSAID use, or is at high risk of developing gastric ulceration. In such patients, misoprostol may be prescribed if the patient has had a negative serum pregnancy test within 2 weeks prior to beginning therapy; is capable of complying with effective contraceptive measures; has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential if the drug is taken by mistake; and will begin misoprostol only on the second or third day of the next normal menstrual period. Due to the abortifacient property of this medication, patients must be warned not to give this drug to others.

Misoprostol is FDA approved for the medical termination of pregnancy of ≤70 days in conjunction with mifepristone.

Because misoprostol may induce or augment uterine contractions, it has been used off-label as a cervical-ripening agent for induction of labor. Misoprostol should not be used for this purpose during the third trimester in conditions where a spontaneous labor and vaginal delivery would be contraindicated, including women who have had a prior cesarean delivery or major uterine surgery (because the risk of uterine rupture is increased) (ACOG 107 2009; ACOG 184 2017). It has also been used for the treatment of incomplete or missed abortion (ACOG 427 2009), early pregnancy loss (ACOG 150 2015), or severe postpartum hemorrhage (ACOG 183 2017; FIGO 2012a; FIGO 2012b). Some guidelines recommend misoprostol for postpartum hemorrhage only secondary to oxytocin in situations where oxytocin is not available (Leduc 2000; FIGO 2012a; FIGO 2012b). Various routes of administration have been used for postpartum hemorrhage. Sublingual administration has the most rapid onset, the oral route produces the most pronounced initial increase in tonus, and rectal and vaginal routes exhibit longer durations of action as compared to oral and sublingual routes (Leduc 2009). Adverse events associated with off-label obstetric uses include uterine tachysystole (may impair placental blood flow), uterine rupture, amniotic fluid embolism, or adverse fetal heart changes. Chills, fever, and/or shivering are commonly associated with use of sublingual misoprostol when used for postpartum hemorrhage; incidence of side effects may be dose related (FIGO 2012b).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.